Cancer is the leading cause of death in Korea, which can occur in all parts of the body and can also be caused by various factors such as environmental factors and genetic factors. There have been many studies to conquer cancer, but it is an incurable disease that has not yet been conquered. Existing therapies for cancer include surgery, chemotherapy, radiation therapy, etc, and the prognosis is improving with the advance of medicine, but there are many limitations that can adversely affect normal cells as well as cancer cells. In recent years, other therapies whose concept is different from these therapies have been studied and, among other things, gene therapies for effectively treating only cancer cells have been actively studied.
The term “gene therapy” refers to a method of treating inherited or acquired genetic abnormalities, which are difficult to treat by conventional methods, using genetic engineering methods. Specifically, gene therapy comprises administering genetic materials such as DNA and RNA into the human body to express therapeutic proteins or inhibit the expression of specific proteins in order to treat and prevent inherited or acquired genetic defects, viral diseases, or chronic diseases such as cancer or cardiovascular diseases. Gene therapy can fundamentally treat diseases by analyzing the causes of diseases on a genetic basis and thus is expected to treat incurable diseases and is also potential as an alternative to conventional therapeutic methods.
Moreover, cancer tissue-targeted therapy has been attempted in an effort to reduce side effects that occur because a number of target genes that can be used in gene therapy are also expressed in normal cells that undergo significant cell division (Fukuzawa et al., Cancer Res 64: 363-369, 2004). For this end, a method of using a tissue-specific promoter instead of CMV or RSV has been proposed, but this method has not been put to practical use due to its low therapeutic efficacy, despite the increased specificity increases.
In addition, studies have recently been conducted to develop a tissue-specific adenovirus for cancer therapy using factors other than the tissue-specific promoter, and as a typical example, a method of using a trans-splicing ribozyme, etc. has been developed.
Studies on the development of a tissue-specific adenovirus for cancer therapy using the trans-splicing ribozyme have demonstrated that the group I intron ribozyme from Tetrahymena thermophila can perform trans-splicing reactions to link two separate transcripts in vitro as well as in bacterial cells and human cells, and thus have attracted much attention.
Specifically, the trans-splicing ribozyme based on this group I intron can target a disease-related gene transcript or a specific RNA that is specifically expressed in diseased cells, causing reprogramming such that the RNA can be restored to a normal RNA or the transcript can be replaced with a new therapeutic gene transcript, and thus it is expected that the trans-splicing ribozyme can be a disease-specific and safe gene therapy technology. In addition, the trans-splicing ribozyme can remove disease-specific RNA and, at the same time, induce the expression of desired therapeutic gene product, thereby increasing the therapeutic effect.
In recent studies, a trans-splicing ribozyme that targets human telomerase reverse transcriptase (hTERT) capable of acting specifically on cancer tissue has been known, and thus attempts to develop cancer therapeutic agents using this trans-splicing ribozyme have been actively made. However, it exhibits high tissue specificity due to a combination with a tissue-specific promoter, but the expression efficiency is low, and thus the disadvantage of low therapeutic efficiency has not yet been overcome. Moreover, in the case of treatment targeting hTERT, it shows telomerase activity also in normal cells such as stem cells, hematopoietic stem cells, germ cells, and regenerating normal liver cells, causing toxicity to normal tissues.